Phenotypic Variability in Marfan Syndrome in a Family With a Novel Nonsense FBN1 Gene Mutation

Introduction: Left ventricular non-compaction cardiomyopathy (LVNC) is a rare and unique cardiomyopathy. Its presentation can range from a benign phenotype to overt heart failure and sudden cardiac death. The genetics of LVNC are not completely understood and current genetic testing has a yield of about 30% in identifying a causative gene mutation. We present a series of patients with LVNC and fibrillin-1 (FBN1) gene mutations. Hypothesis: We hypothesize that FBN1 gene mutations can lead to LVNC by way of its role in the myocardial extracellular matrix during cardiac development. Methods: A retrospective review of all patients with LVNC at our institution was performed for purposes of another investigation. The process unexpectedly identified patients with LVNC and FBN1 gene mutations, as well as LVNC and Marfan syndrome. Results: Approximately 150 patients are followed in our clinic with LVNC. We screened this population and found 51 patients on medical therapy for reduced function. We retrospectively reviewed gene testing in these 51 patients, when available, and identified 5 patients (10%) with an FBN1 gene mutation. All 5 patients had a dilated LVNC phenotype and previous or current evidence of left ventricular dysfunction. Syndrome breakdown as follows: 3 with Marfan, 1 with Shprintzen-Goldberg, and 1 with no identifiable syndrome. Dilated cardiomyopathy/LVNC gene testing was performed in 3 patients; 2 had disease causing myosin heavy chain 7 gene defects and 1 had no defects. Conclusions: The role of FBN1 in the human myocardium is not completely understood but it is expressed in the developing fetal heart and is a component of the myocardial extracellular matrix. Although causation has not been proven by our report, it certainly raises interest in a mechanistic relationship between LVNC and FBN1 given the increased prevalence of Marfan syndrome and probable increased prevalence of FBN1 gene mutations in this cohort of LVNC patients in light of FBN1.

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The effect of beta-blockers therapy on progression of thoracic aortic dilatation in the young Marfan syndrome patients: Difference between subtypes of FBN1 gene mutation

Archives of Cardiovascular Diseases Supplements ◽

10.1016/j.acvdsp.2018.06.031 ◽

2018 ◽

Vol 10 (3-4) ◽

pp. 287-288

Author(s):

Ngoc-Thanh Kim ◽

Julie Plaisancie ◽

Thomas Edouard ◽

Miarisoa Ratsimandresy ◽

Philippe Acar ◽

...

Keyword(s):

Gene Mutation ◽

Marfan Syndrome ◽

Beta Blockers ◽

Aortic Dilatation ◽

Fbn1 Gene

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A Recurring FBN1 Gene Mutation in Neonatal Marfan Syndrome

Archives of Pediatrics and Adolescent Medicine ◽

10.1001/archpedi.156.11.1081 ◽

2002 ◽

Vol 156 (11) ◽

pp. 1081 ◽

Cited By ~ 28

Author(s):

Amanda M. Jacobs ◽

Ivanka Toudjarska ◽

Andrew Racine ◽

Petros Tsipouras ◽

Michael W. Kilpatrick ◽

...

Keyword(s):

Gene Mutation ◽

Marfan Syndrome ◽

Fbn1 Gene ◽

Neonatal Marfan Syndrome

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Reference Expression Profile of Three FBN1 Transcript Isoforms and Their Association with Clinical Variability in Marfan Syndrome

Genes ◽

10.3390/genes10020128 ◽

2019 ◽

Vol 10 (2) ◽

pp. 128

Author(s):

Louise Benarroch ◽

Mélodie Aubart ◽

Marie-Sylvie Gross ◽

Pauline Arnaud ◽

Nadine Hanna ◽

...

Keyword(s):

Marfan Syndrome ◽

Age Of Onset ◽

Expression Profiles ◽

Phenotypic Variability ◽

Surrogate Endpoint ◽

Connective Tissue Disorder ◽

Clinical Variability ◽

Fbn1 Gene ◽

Adventitial Fibroblasts ◽

Alternatively Spliced

Marfan syndrome (MFS) is a rare connective tissue disorder mainly due to mutations in the FBN1 gene. Great phenotypic variability is notable for age of onset, the presence and absence, and the number and the severity of the symptoms. Our team showed that FBN1 gene expression level was a good surrogate endpoint for severity of some MFS clinical features. Eight alternative transcripts are referenced for the FBN1 gene. We hypothesized that MFS clinical variability could be related to specific FBN1 isoforms. Isoform expression profiles were investigated in skin and adventitial fibroblasts from controls and MFS patients. The results of the study showed that, in skin and adventitial fibroblasts, only three isoforms were found: FBN1_001, FBN1_004, and FBN1_009. The main isoform was FBN1_001 and it was significantly reduced in skin and adventitial fibroblasts of MFS patients. The expressions of FBN1_004 and FBN1_009 isoforms were similar between controls and MFS patients. However, the expression of the three isoforms was correlated only in patients. Furthermore, their expression levels were associated with the presence of ectopia lentis in MFS patients. Therefore, our results highlight that the two minor alternatively spliced FBN1 isoforms play a possible role in the pathogenesis of the disease.

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A novel FBN1 gene mutation associated with earlyonset pneumothorax in Marfan syndrome

Journal of Genetic Medicine ◽

10.5734/jgm.2016.13.1.41 ◽

2016 ◽

Vol 13 (1) ◽

pp. 41-45

Author(s):

Min Ji Park ◽

Dong Hun Lee ◽

Young Lim Shin ◽

Yong Hee Hong

Keyword(s):

Gene Mutation ◽

Marfan Syndrome ◽

Fbn1 Gene

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Family history of aortic dissection is not a risk factor in Marfan syndrome with a FBN1 gene mutation

European Heart Journal ◽

10.1093/eurheartj/ehab724.2009 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

Author(s):

M Tchitchinadze ◽

O Milleron ◽

L Eliahou ◽

S Jadoui ◽

N Ould Ouali ◽

...

Keyword(s):

Risk Factor ◽

Family History ◽

Aortic Dissection ◽

Gene Mutation ◽

Marfan Syndrome ◽

Aortic Surgery ◽

Aortic Disease ◽

Personal Risk ◽

Fbn1 Gene ◽

History Of

Abstract Background A history family of aortic dissection was considered as a risk factor for aortic dissection in patients with Marfan syndrome with a FBN1 mutation. Objectives Evaluate whether a family history of aortic dissection is a risk marker for dissection in this population Methods Retrospective study of patients coming to the reference centre between 1996 and 2018, carrying a FBN1 gene mutation. Pedigrees were obtained for each patient, and familial screening actively pursued. Patients with a family history of aortic dissection were compared with patients without family history of aortic dissection. Results 1700 patients (age 33.2 (±17) years, 51% women) with a FBN1 gene mutation were included. 145 (8,5%) patients underwent aortic dissection at a mean age of 37.9 (±11.4) years and 323 (19%) patients had been operated at 33.8 (±13.9) years. 481 patients had a family history of aortic dissection, including 38 who dissected themselves, and 88 who underwent surgery. 1219 had no family history of aortic dissection, including 107 who dissected themselves, and 235 who underwent surgery. Therefore, the personal risk for aortic dissection was similar in patients with and without a family history of aortic dissection (38/481, i.e. 7.9% vs 107/1219, i.e. 8.8%), as was the personal risk for prophylactic aortic surgery (88/481, i.e. 18.3% vs. 253/1219, i.e. 17.2%), and the risk for either aortic dissection or prophylactic aortic surgery (118/481, i.e. 24.5% vs. 328/1219, i.e. 26.9%). Conclusions In Marfan syndrome with a FBN1 gene mutation, a family history of aortic dissection is not a marker of aortic disease severity. FUNDunding Acknowledgement Type of funding sources: None.

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Large phenotypic variability of diabetes due to ABCC8 gene mutation illustrated by the paradigm of a family

Endocrine Abstracts ◽

10.1530/endoabs.63.p192 ◽

2019 ◽

Author(s):

Theocharis Koufakis ◽

Amalia Sertedaki ◽

Elizabeth-Barbara Tatsi ◽

Christina-Maria Trakatelli ◽

Spyridon Karras ◽

...

Keyword(s):

Gene Mutation ◽

Phenotypic Variability ◽

Abcc8 Gene

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Unsuspected somatic mosaicism for FBN1 gene contributes to Marfan syndrome

Genetics in Medicine ◽

10.1038/s41436-020-01078-6 ◽

2021 ◽

Author(s):

Pauline Arnaud ◽

Hélène Morel ◽

Olivier Milleron ◽

Laurent Gouya ◽

Christine Francannet ◽

...

Keyword(s):

Marfan Syndrome ◽

Somatic Mosaicism ◽

Variant Calling ◽

Copy Number Variations ◽

Pathogenic Variant ◽

Single Nucleotide Variants ◽

Bioinformatics Analyses ◽

Single Nucleotide ◽

Fbn1 Gene ◽

Pathogenic Variants

Abstract Purpose Individuals with mosaic pathogenic variants in the FBN1 gene are mainly described in the course of familial screening. In the literature, almost all these mosaic individuals are asymptomatic. In this study, we report the experience of our team on more than 5,000 Marfan syndrome (MFS) probands. Methods Next-generation sequencing (NGS) capture technology allowed us to identify five cases of MFS probands who harbored a mosaic pathogenic variant in the FBN1 gene. Results These five sporadic mosaic probands displayed classical features usually seen in Marfan syndrome. Combined with the results of the literature, these rare findings concerned both single-nucleotide variants and copy-number variations. Conclusion This underestimated finding should not be overlooked in the molecular diagnosis of MFS patients and warrants an adaptation of the parameters used in bioinformatics analyses. The five present cases of symptomatic MFS probands harboring a mosaic FBN1 pathogenic variant reinforce the fact that apparently asymptomatic mosaic parents should have a complete clinical examination and a regular cardiovascular follow-up. We advise that individuals with a typical MFS for whom no single-nucleotide pathogenic variant or exon deletion/duplication was identified should be tested by NGS capture panel with an adapted variant calling analysis.

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